Vogt–Koyanagi–Harada (VKH) Disease: A Multisystem Inflammatory Disorder and Its Association with COVID-19

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Vogt–Koyanagi–Harada (VKH) disease, a rare and complex multisystem inflammatory disorder, impacts various organs, including the eyes, ears, brain, skin, and hair. In recent times, there has been growing interest in exploring its potential association with the Coronavirus Disease 2019 (COVID-19) and the COVID-19 vaccination, particularly due to reported cases linking these events.

This article provides a comprehensive overview of VKH disease, delves into the literature surrounding VKH cases following COVID-19 infection and vaccination, and shares insights from our own experiences.

While cases of VKH disease associated with COVID-19 and vaccination are emerging, this article emphasizes that a good response to therapy should not deter individuals from getting vaccinated.

However, it also highlights the need for vigilance among ophthalmologists, especially in genetically predisposed subjects.

As the intricate relationship between VKH disease and COVID-19 unfolds, several key points emerge, highlighting the need for ongoing research and vigilance:

Trigger Mechanism: The association between VKH disease and COVID-19 suggests a potential triggering mechanism. Just as other viral infections have been implicated in VKH onset, the SARS-CoV-2 virus may be acting as a trigger in susceptible individuals. Further investigation is required to elucidate the precise mechanisms by which the virus might initiate or exacerbate VKH disease.

COVID-19 Vaccines: The occurrence of VKH disease following COVID-19 vaccination underscores the complexity of immune responses elicited by these vaccines. While vaccines are crucial in combatting the pandemic, it’s essential to monitor and investigate potential side effects, including autoimmune reactions like VKH. This information can aid in refining vaccine formulations and understanding their safety profiles.

Immunosuppressive Therapy: Many VKH patients were already receiving immunosuppressive therapy at the time of vaccination. This raises questions about whether certain medications or combinations thereof may influence the risk of VKH following COVID-19 vaccination. Careful consideration of treatment regimens and patient profiles is essential.

Gender and Age Factors: The preponderance of VKH cases among females and variations in age at onset necessitate deeper exploration. Understanding how gender and age may influence VKH susceptibility can provide valuable insights into the disease’s pathogenesis.

Temporal Associations: The temporal relationship between COVID-19 vaccination or infection and the onset of VKH symptoms cannot be ignored. Analyzing these intervals and their variability may help identify potential windows of heightened risk.

Response to Therapy: The effectiveness of systemic corticosteroid therapy in treating VKH cases following COVID-19 vaccination or infection is noteworthy. This suggests that early intervention and appropriate management can lead to favorable outcomes, even in challenging scenarios.

Incidence During the Pandemic: The lack of a substantial increase in VKH incidence during the COVID-19 pandemic, at least in some regions, is an intriguing finding. This observation raises questions about environmental factors, population demographics, and potential protective effects that may influence disease occurrence.

Background

VKH disease, also known as Vogt–Koyanagi–Harada syndrome, is a rare autoimmune disorder characterized by its wide-ranging inflammatory effects on multiple organs, notably the eyes. The disease’s etiology is multifaceted, with factors such as viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its vaccine, being considered as potential triggers.

COVID-19, caused by the novel coronavirus SARS-CoV-2, has had a profound impact worldwide, affecting health and economies. It is now under scrutiny for its possible links to autoimmune diseases, including VKH. This article aims to review all reported cases of VKH disease following COVID-19 infection and vaccination, investigate potential pathogenic mechanisms, and provide insights based on our experiences.

Epidemiology

VKH disease exhibits varying global prevalence, with higher incidence among pigmented races, such as Asians, Middle Easterners, Hispanics, and Native Americans, while being sporadic in Africa. The condition is more common in women, and onset typically occurs between the second and fifth decades of life. However, pediatric cases and late-onset VKH have also been documented.

In Italy, VKH disease is predominantly diagnosed in women (77.7% of cases), with an average age of onset around 32.6 years. Importantly, 18% of patients in the same cohort were under 16 years old at disease onset, underscoring its potential impact on young individuals.

Pathogenesis

VKH disease is classified as a T-cell autoimmune disorder primarily targeting choroidal melanocytes expressing class II major histocompatibility complex (MHC) antigens, particularly tyrosinase peptides involved in melanin synthesis. A significant association exists between VKH and MHC class II genes, notably the human leukocyte antigen HLA-DR4, across various ethnic groups.

The immune response in VKH centers on CD4+ and Th17 T cell subsets targeting MHC class II loaded with melanocyte antigens. However, the exact mechanisms triggering tolerance loss to these self-proteins remain elusive, representing a challenging aspect of disease pathogenesis.

One hypothesis suggests that CD4+ T-cells sensitized to viral peptides might cross-react with tyrosinase peptides via molecular mimicry, a phenomenon observed in other viral infections associated with VKH disease. Various viral agents, including hepatitis B, hepatitis C, cytomegalovirus (CMV), and Epstein–Barr virus (EBV), have been implicated.

Vaccination has also been linked to VKH onset, with cases reported following hepatitis, human papillomavirus, influenza, yellow fever, and Bacillus Calmette-Guerin vaccines. Three proposed mechanisms include direct eye infection by live vaccines, molecular mimicry between vaccine particles and ocular structures, and autoimmune uveitis triggered by vaccine adjuvants or additives.

VKH and COVID-19

In recent times, VKH cases following COVID-19 infection and vaccination have emerged. Though the sample size is limited, and symptom onset varies widely after vaccination, there is growing concern about the relationship between these events and the molecular factors involved.

A direct connection between uveitis and vaccines, including COVID-19 vaccines, is challenging to establish. The Naranjo Scale, an algorithm for assessing causality between clinical events and drugs, helps evaluate the probability of such a link.

Typical Clinical Features

VKH disease exhibits a broad spectrum of clinical features that can involve the eyes, central nervous system, skin, and auditory system. These features can evolve over time and are often characterized by distinct stages:

Prodromal Stage

  • Duration: Typically lasts 3–5 days.
  • Symptoms: Patients experience nonspecific symptoms such as malaise, fever, nausea, headache, and dizziness.
  • Neurological Symptoms: Some may develop neurological symptoms like cranial nerve palsies, hemiparesis, transverse myelitis, and optic neuritis.
  • Eye-related Symptoms: Photophobia, tearing, and hypersensitivity of hair and scalp may be reported.

Acute Uveitic Stage

  • Onset: Occurs a few days after the prodromal phase and persists for several weeks.
  • Eye Symptoms: Blurred vision, pain, and central scotoma are predominant complaints.
  • Posterior Uveitis: Most patients present with bilateral posterior uveitis.
  • Ocular Findings: Thickening of the posterior choroid, hyperemia, optic disc edema, circumscribed retinal edema, and diffuse serous retinal detachment may be observed.
  • Anterior Segment Involvement: Granulomatous iridocyclitis, mutton-fat keratic precipitates, iris nodules, and anterior chamber shallowing can follow.

Chronic (or Convalescent) Stage

  • Duration: Lasts for months or even years.
  • Skin Manifestations: Integumentary changes, including vitiligo, poliosis (loss of pigmentation of hair), and alopecia (hair loss), become evident.
  • Sugiura’s Sign: Perilimbal depigmentation, a sign seen mainly in Japanese subjects, may appear in the first month after uveitis onset.
  • Retinal Changes: RPE scars in the mid-periphery of the retina and hypopigmented lesions surrounded by pigment may develop.
  • Fundus Appearance: The fundus can take on a light orange-reddish appearance, often referred to as ‘sunset glow fundus.’

Chronic Recurrent Stage

  • Recurrence: Characterized by recurrent, primarily anterior granulomatous uveitis.
  • Choroidal Examination: Indocyanine green angiography (ICGA) and optical coherence tomography (OCT) can reveal active choroiditis.
  • Complications: This stage can lead to complications such as glaucoma, cataracts, retinal neovascularization, subretinal fibrosis, and subretinal neovascularization.

Extra-Ocular Manifestations

VKH disease is not limited to ocular involvement; it can affect various extraocular systems, including the integumentary, central nervous, and auditory systems. The severity and frequency of these manifestations may vary based on factors such as ethnicity and timely treatment:

Integumentary Manifestations

  • Prodromal Stage: Hypersensitivity to hair and scalp.
  • Chronic Stage: Vitiligo, alopecia, and poliosis (often involving the face, eyelids, and trunk).
  • Sugiura’s Sign: Perilimbal depigmentation.
  • Skin Involvement in VKH: Skin manifestations are reported in a significant proportion of patients, with alopecia occurring in about one-third of subjects.

Central Nervous System Involvement

  • Prodromal Stage: Symptoms include sterile meningitis (neck stiffness, headache), encephalitis (convulsions, altered consciousness), and cranial neuropathies.
  • Headaches: Notably different from the initial prodromal symptoms and can affect a majority of VKH patients.

Auditory System

  • Prodromal Stage: Common inner ear problems include tinnitus, hearing loss, and vertigo.
  • Hearing Loss: Typically cochlear hearing loss that improves in a few months.

VKH disease’s multifaceted nature highlights the need for a comprehensive approach to diagnosis and management, with particular attention to the diverse clinical manifestations and stages. Timely intervention is crucial in preventing complications and ensuring favorable outcomes for patients affected by this challenging autoimmune disorder.

Therapeutic Approaches

The primary objective in treating VKH disease, especially in its early stages, is to suppress intraocular inflammation, particularly in the acute posterior uveitic/exudative stage. Key therapeutic considerations include:

High-Dose Systemic Corticosteroids

  • Initial Response: VKH typically responds well to high-dose systemic corticosteroid therapy in the acute phase.
  • Timing: Initiating treatment early (from two weeks onwards) in severe cases can significantly reduce disease duration, limit extraocular manifestations, improve final visual acuity, and prevent progression to the chronic stage.

Minimum Treatment Duration

  • Relapse Prevention: The abrupt discontinuation of systemic corticosteroids can lead to relapses.
  • Treatment Period: Studies indicate that a minimum treatment duration of six months is crucial for preventing relapses and reducing their severity.
  • Evidence: Researchers like Lai and Errera have demonstrated the significance of the six-month treatment period in reducing the frequency and severity of relapses.

Immunosuppressive Therapy

  • Combination Therapy: Immunomodulatory agents such as methotrexate, mycophenolate mofetil, azathioprine, cyclosporine A, or alkylating agents can be introduced at various stages of VKH.
  • Goals: These agents enhance the potency of corticosteroid therapy, reduce the overall corticosteroid dosage required for disease control, and become especially relevant when corticosteroids are contraindicated due to underlying systemic conditions (e.g., diabetes).
  • Benefits: Studies have shown that combining immunosuppressive therapy with corticosteroids reduces the recurrence of uveitis, the development of late complications, and improves visual acuity in patients during the acute stage.

Timing of Immunomodulatory Therapy

  • Early Intervention: Some authors recommend initiating immunosuppressive therapy within two to three weeks of symptom onset to achieve better outcomes.
  • Combined Therapy: Combined treatment has been associated with a lower incidence of complications like “sunset glow fundus,” which is linked to a higher risk of complications and a poorer visual prognosis.

Personalized Approach

  • Patient-Specific Response: It’s important to note that while combination therapy is often effective, some patients may experience significant recovery with corticosteroid therapy alone.
  • Risk of Overtreatment: Treating all VKH patients with immunosuppressive agents might lead to overtreatment and expose individuals to unnecessary side effects.

Prognosis Factors

The visual prognosis for VKH patients has substantially improved with advances in therapy and complication management. Several factors have been correlated with the final visual prognosis:

Timely Treatment

  • Persistent Inflammation: Late initiation or delayed therapy tends to result in more persistent inflammation.
  • Duration of Treatment: A treatment duration of less than six months is significantly associated with worse final visual acuity.
  • Dose of Corticosteroids: A high corticosteroid dose administered during the acute phase can preserve more melanocytes, limiting damage.

Patient Characteristics

  • Age at Onset: Prognosis varies regarding age at onset; some studies suggest worse outcomes in older patients, while others indicate the prognosis might be worse in younger individuals.
  • HLA-DRB1*0405/0410: Some variations in HLA-DR4 gene variants are associated with longer disease duration.

Clinical Features

  • Visual Acuity at Presentation: Eyes with better visual acuity at the onset of VKH are more likely to have better final visual acuity.
  • Complications: The presence of complications is linked to worse final visual acuity.
  • Number of Relapses: Multiple relapses increase the risk of complications and worsen the visual prognosis due to prolonged exposure to inflammation and treatment, especially corticosteroids.

Conclusion

VKH disease, a rare autoimmune disorder with systemic manifestations, is increasingly being associated with COVID-19 infection and vaccination. Although the exact mechanisms remain unclear, there is evidence of molecular mimicry and autoimmune responses contributing to VKH onset.

Despite these associations, it is crucial to emphasize the importance of COVID-19 vaccination. VKH patients appear to respond well to corticosteroid therapy, resulting in a favorable visual prognosis. However, ophthalmologists should remain vigilant, especially in genetically predisposed individuals, to monitor and manage VKH cases following COVID-19 vaccination.

In conclusion, while VKH disease is among the uveitic entities reported after COVID-19 vaccination, the benefits of vaccination far outweigh the potential risks. Future research should continue to investigate the complex interplay between viral infections, vaccines, genetics, and autoimmune diseases like VKH to advance our understanding of these phenomena.


reference link : https://www.mdpi.com/2077-0383/12/19/6242

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